RESUMEN

Extraintestinal pathogenic Escherichia coli (ExPEC) can lead to severe infections, with additional risks of increasing antimicrobial resistance rates. Genotypic similarities between ExPEC and avian pathogenic E. coli (APEC) support a possible role for a poultry meat reservoir in human disease. Some genomic studies have been done on the ST117 lineage which contaminates poultry meat, carries multidrug resistance, can be found in the human intestinal microbiota, and causes human extraintestinal disease. This study analyzed the genomes of 61 E. coli from Brazilian poultry outbreaks focusing on ST117, to further define its possible zoonotic characteristics by genotypic and phylogenomic analyses, along with 1,699 worldwide ST117 isolates originating from human, animal, and environment sources. A predominance of ST117 was detected in the Brazilian isolates (n = 20/61) frequently carrying resistance to critical antibiotics (>86%) linked to IncFII, IncI1, or IncX4 replicons. High similarities were found between IncX4 from Brazilian outbreaks and those from E. coli recovered from imported Brazilian poultry meat and human clinical cases. The ST117 phylogeny showed non-specificity according to host and continent and an AMR index score indicated the highest resistance in Asia and South America, with the latter statistically more resistant and overrepresented with resistance to extended-spectrum beta-lactamases (ESBL). Most ST117 human isolates were predicted to have a poultry origin (93%, 138/148). In conclusion, poultry is a likely source for zoonotic ExPEC strains, particularly the ST117 lineage which can also serve as a reservoir for resistance determinants against critical antibiotics encoded on highly transmissible plasmids. IMPORTANCE: Certain extraintestinal pathogenic Escherichia coli (ExPEC) are particularly important as they affect humans and animals. Lineages, such as ST117, are predominant in poultry and frequent carriers of antibiotic resistance, presenting a risk to humans handling or ingesting poultry products. We analyzed ExPEC isolates causing outbreaks in Brazilian poultry, focusing on the ST117 as the most detected lineage. Genomic comparisons with international isolates from humans and animals were performed describing the potential zoonotic profile. The Brazilian ST117 isolates carried resistance determinants against critical antibiotics, mainly on plasmids, in some cases identical to those carried by international isolates. South American ST117 isolates from all sources generally exhibit more resistance, including to critical antibiotics, and worldwide, the vast majority of human isolates belonging to this lineage have a predicted poultry origin. As the world's largest poultry exporter, Brazil has an important role in developing strategies to prevent the dissemination of multidrug-resistant zoonotic ExPEC strains.

RESUMEN

A previous study using miRNA sequencing revealed that exposure to a mixture of phthalates during pregnancy and lactation dysregulated rno-miR-184 and rno-miR-141-3p in the ventral prostate (VP) of offspring. Here, rno-miR-184 and rno-miR-141-3 expressions were obtained by RT-qPCR in the VP of F1 males as well as in F2 offspring, aiming to establish a relationship with possible oncogenic targets through in silico analyses with multigenerational approach. Additionally, some targets were measured by western blots to highlight a possible relationship between the deregulated miRNAs and some of their targets. VP samples from rats exposed to a mixture of phthalates maternally during pregnancy and lactation (GD10 to PND21-F1) and VP from offspring (F2) were examined. The phthalate mixture at both concentrations (20 µg and 200 mg/kg/day) increased the expression of both miRNAs in the F1 (PND22 and 120) and F2 (descendants of F1-treated males) prostate. Target prediction analysis revealed that both microRNAs are responsible for modulating the expression and synthesis of 40 common targets. A phthalate target association analysis and the HPA database showed an interesting relationship among these possible miRNAs modulated targets with prostate adenocarcinoma and other oncogenic processes. Western blots showed alteration in P63, P53, WNT5, and STAT3 expression, which are targeted by the miRNAs, in the VP of F1/F2 males. The data draw attention to the epigenetic modulation in the prostate of descendants exposed to phthalates and adds to one of the few currently found in the literature to point to microRNAs signature as biomarkers of exposure to plasticizers.

Asunto(s)

MicroARNs , Ácidos Ftálicos , Efectos Tardíos de la Exposición Prenatal , Neoplasias de la Próstata , MicroARNs/genética , MicroARNs/metabolismo , Masculino , Animales , Neoplasias de la Próstata/inducido químicamente , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Femenino , Ácidos Ftálicos/toxicidad , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/genética , Exposición Materna/efectos adversos , Próstata/efectos de los fármacos , Próstata/patología , Ratas Wistar , Ratas , Simulación por Computador

RESUMEN

INTRODUCTION: Cardiac biomarkers can be useful in understanding the systemic and heart manifestations of sickle cell disease (SCD). Biomarkers reflect various aspects of heart disease (remodeling, injury and myocardial strain), with discriminatory potential for non-cardiac complications. Patients and METHODS: SCD patients (SS/Sß0) in steady state, were studied, correlating clinical manifestations and echo parameters (myocardial work - MW and speckle tracking), pre-MSCD severity score (integrating clinical and echo data), and cardiac biomarkers (high-sensitivity troponins ­ hs-cTn I and T, NT-pro-BNP, ST2s, and galectin-3 - GAL3). Quantitative characteristics were analyzed by Spearman tests, and qualitative characteristics by Mann-Whitney test. Hemolytic Index (HI) was calculated through Principal Component Analysis. Generalized linear Poisson models were generated for hs-cTn, and γ-distribution models were employed for other markers, with final models selected through the Stepwise Backward method. RESULTS: We studied 126 patients (mean age 37.2 ± 11.6 years), 42.1% male, and 80.2% SS. 47% were on hydroxyurea treatment and 30.2% on a chronic transfusion. NT-pro-BNP was elevated in 44% (> 160 ng/mL in 37%), correlated with female gender (p < 0.001), severity score (p = 0.001), uric acid (p = 0.017), HI (p < 0.001), Global Work Index (GWI) (p = 0.003), left atrial (LA) stiffness (p = 0.003), and ventricular mass (VM) (p = 0.02). ST2s were elevated in 11% and correlated with male gender (p > 0.001), HI (p > 0.001), cardiac index (p = 0.015), and LA strain reservoir function (p = 0.034). GAL3 was elevated in 42.8%, correlated with E/e'ratio (p = 0.006), uric acid (p = 0.005), and absence of chronic pain (p = 0.046). hs-cTn correlated with age (c-TnI p = 0.004; c-TnT p > 0.001), HI (p > 0.001), diastolic dysfunction (p > 0.001), left VM (p < 0.001), increased GWI (p < 0.001), and reduced MW efficiency (p < 0.001). hs-cTn I also correlated with increased LA reservoir function (p < 0.001) with reduced conduit function (p < 0.001). hs-cTn T correlated with uric acid (p = 0.001), and in univariate analysis was also correlated with severity score. The values of both hs-cTn correlated with increased GWI (p < 0.001) and reduced MW efficiency (p < 0.001). DISCUSSION: The biomarkers demonstrated various clinical and pathophysiological aspects of SCD. NT-pro-BNP is a routine marker with correlations similar to literature, except for higher values in females, also observed in non-SCD population. ST2 and GAL3 had limited correlations with echo findings, likely due to their production in extracardiac tissues affected by inflammation/vaso-occlusion. Both were linked to the HI, and the decrease in GAL3 in chronic pain can be attributed to chronic opioid use causing reduced synthesis of it. The elevation of hs-cTn was expected due to the analytical characteristics of high-sensitivity assays, but low in terms of the extent of heart involvement. hs-cTnT was more associated with general severity, like in the general population, where it is associated with overall mortality, while hs-cTnI is more connected to heart disease. MW in SCD is optimized to the maximum with a very low Global Work Wasted, and hs-cTn elevation is associated with reduced MW efficiency, indicating mecano-energetic uncoupling and subtle systolic dysfunction. CONCLUSION: Our study demonstrates that cardiac biomarkers can be used for clinical and pathophysiological evaluation, with NT-pro-BNP confirming its role in clinical stratification. ST2s and GAL3 may reveal new pathophysiological pathways in hemolysis and the interaction of opioids and chronic pain. Troponins are promising as prospective tool and may unveil ischemic damage resulting from myocardial mecano-energetic dissociation.

Asunto(s)

Ecocardiografía , Enfermedades Cardiovasculares

RESUMEN

As the second leading cause of death for cancer among men worldwide, prostate cancer (PCa) prevention and detection remain a critical challenge. One aspect of PCa research is the identification of common environmental agents that may increase the risk of initiation and progression of PCa. Endocrine disrupting chemicals (EDCs) are strong candidates for risk factors, partially because they alter essential pathways for prostate gland development and oncogenesis. Phthalates correspond to a set of commercially used plasticizers that humans are exposed to ubiquitously. Here, we show that maternal exposure to a phthalate mixture interferes with the expression profile of mRNA and proteins in the ventral prostate of offspring and increases the susceptibility to prostate adenocarcinomas in aged animals. The data highlight Ubxn11, Aldoc, Kif5c, Tubb4a, Tubb3, Tubb2, Rab6b and Rab3b as differentially expressed targets in young and adult offspring descendants (PND22 and PND120). These phthalate-induced targets were enriched for pathways such as: dysregulation in post-translational protein modification (PTPM), cell homeostasis, HSP90 chaperone activity, gap junctions, and kinases. In addition, the Kif5c, Tubb3, Tubb2b and Tubb4a targets were enriched for impairment in cell cycle and GTPase activity. Furthermore, these targets showed strong relationships with 12 transcriptional factors (TF), which regulate the phosphorylation of eight protein kinases. The correlation of TF-kinases is associated with alterations in immune system, RAS/ErbB/VEGF/estrogen/HIF-1 signaling pathways, cellular senescence, cell cycle, autophagy, and apoptosis. Downregulation of KIF5C, TUBB3 and RAB6B targets is associated with poor prognosis in patients diagnosed with adenocarcinoma. Collectively, this integrative investigation establishes the post-transcriptional mechanisms in the prostate that are modulated by maternal exposure to phthalate mixture during gestation and lactation.

Asunto(s)

Neoplasias de la Próstata , Proteoma , Animales , Humanos , Masculino , Embarazo , Ratas , Biomarcadores , Lactancia , Neoplasias de la Próstata/inducido químicamente , Neoplasias de la Próstata/genética , Transcriptoma , Femenino , Exposición Materna/efectos adversos

RESUMEN

DiGeorge syndrome is a disorder caused by a microdeletion on the long arm of chromosome 22. Approximately 1% of patients diagnosed with DiGeorge syndrome may have an absence of a functional thymus, which characterizes the complete form of the syndrome. These patients require urgent treatment to reconstitute T cell immunity. Thymus transplantation is a promising investigational procedure for reconstitution of thymic function in infants with congenital athymia. Here, we demonstrate a possible optimization of the preparation of thymus slices for transplantation through prior depletion of thymocytes and leukocyte cell lineages followed by cryopreservation with cryoprotective media (5% dextran FP 40, 5% Me2SO, and 5% FBS) while preserving tissue architecture. Thymus fragments were stored in liquid nitrogen at -196°C for 30 days or one year. The tissue architecture of the fragments was preserved, including the distinction between medullary thymic epithelial cells (TECs), cortical TECs, and Hassall bodies. Moreover, depleted thymus fragments cryopreserved for one year were recolonized by intrathymic injections of 3×106 thymocytes per mL, demonstrating the capability of these fragments to support T cell development. Thus, this technique opens up the possibility of freezing and storing large volumes of thymus tissue for immediate transplantation into patients with DiGeorge syndrome or atypical (Omenn-like) phenotype.

Asunto(s)

Síndrome de DiGeorge , Síndromes de Inmunodeficiencia , Humanos , Timocitos , Síndrome de DiGeorge/terapia , Timo , Células Epiteliales

RESUMEN

Introduction: Microbial systems, such as Escherichia coli, as host recombinant expression is the most versatile and the cheapest system for protein production, however, several obstacles still remain, such as recovery of soluble and functional proteins from inclusion bodies, elimination of lipopolysaccharides (LPS) contamination, incomplete synthesis, degradation by proteases, and the lack of post-translational modifications, which becomes even more complex when comes to membrane proteins, because they are difficult not only to produce but also to keep in solution in its active state. T-cell Immunoglobulin and Mucin domain 3 (TIM-3) is a type I transmembrane protein that is predominantly expressed on the surface of T lymphocytes, natural killer (NK) cells, dendritic cells, and macrophages, playing a role as a negative immune checkpoint receptor. TIM-3 comprises a single ectodomain for interaction with immune system soluble and cellular components, a transmembrane domain, and a cytoplasmic tail, responsible for the binding of signaling and scaffolding molecules. TIM-3 pathway holds potential as a therapeutic target for immunotherapy against tumors, autoimmunity, chronic virus infections, and various malignancies, however, many aspects of the biology of this receptor are still incompletely understood, especially regarding its ligands. Methods: Here we overcome, for the first time, the challenge of the production of active immune checkpoint protein recovered from bacterial cytoplasmic inclusion bodies, being able to obtain an active, and non-glycosylated TIM-3 ectodomain (TIM-3-ECD), which can be used as a tool to better understand the interactions and roles of this immune checkpoint. The TIM-3 refolding was obtained by the association of high pressure and alkaline pH. Results: The purified TIM-3-ECD showed the correct secondary structure and was recognized from anti-TIM-3 structural-dependent antibodies likewise commercial TIM-3-ECD was produced by a mammal cells system. Furthermore, immunofluorescence showed the ability of TIM-3-ECD to bind to the surface of lung cancer A549 cells and to provide an additional boost for the expression of the lymphocyte activation marker CD69 in anti-CD3/CD28 activated human PBMC. Discussion: Taken together these results validated a methodology able to obtain active checkpoint proteins from bacterial inclusion bodies, which will be helpful to further investigate the interactions of this and others not yet explored immune checkpoints.

RESUMEN

Western diet (WD), abundant in saturated fats and simple carbohydrates, has been associated with the development of prostate diseases. In addition, 2,4-dichlorophenoxyacetic acid (2,4-D), an herbicide used in agricultural and non-agricultural settings, may interfere with the endocrine system impacting reproductive health. The association of both factors is something common in everyday life, however, there are no relevant studies associating them as possible modulators of prostatic diseases. This study evaluated the action of the herbicide 2,4-D on the postnatal development of the prostate in mice fed with WD. Male C57Bl/6J mice received simultaneously a WD and 2,4-D at doses of 0.02, 2.0, or 20.0 mg/kg b.w./day for 6 months. The prolongated WD intake induced obesity and glucose intolerance, increasing body weight and fat. WD induced morphological changes and increased PCNA-positive epithelial cells in prostate. Additionally, the WD increased gene expression of AR, antioxidant targets, inflammation-related cytokines, cell repair and turnover, and targets related to methylation and miRNAs biosynthesis compared to the counterpart (basal diet). 2,4-D (0.02 and 2.0) changed prostate morphology and gene expression evoked by WD. In contrast, the WD group exposed to 20 mg/kg of 2,4-D reduced feed intake and body weight, and increased expression of androgen receptor and genes related to cell repair and DNA methylation compared to the negative control. Our results showed that 2,4-D was able to modulate the effects caused by WD, mainly at lower doses. However, further studies are needed to elucidate the mechanisms of 2,4-D on the obesogenic environment caused by the WD.

Asunto(s)

Dieta Occidental , Herbicidas , Masculino , Ratones , Animales , Próstata , Peso Corporal , Herbicidas/toxicidad , Ácido 2,4-Diclorofenoxiacético/toxicidad , Ratones Endogámicos C57BL

RESUMEN

Some high-risk Avian Pathogenic Escherichia coli (APEC) clones have been associated with increased economic losses caused by avian colibacillosis. They may represent an additional food consumption concern due to the potential zoonotic role causing urinary tract infections mainly related to E. coli ST73 and ST95 lineages. This study aimed to characterize APEC isolated from slaughterhouse carcasses presenting lesions compatible with avian colibacillosis. We analyzed about 6500 broilers carcasses, and 48 showed lesions consistent with colibacillosis. Forty-four strains of E. coli were isolated, with 77.27% (n = 34/44) classified as APEC. The isolates belonged to the phylogenetic groups B2 (41.17%, n = 14/34), G (20.59%, n = 7/34), A (17.65%, n = 6/34), B1 (8.82%, n = 3/34), and E (5.88%, n = 2/34). Determining the phylogenetic group of 5.88% (n = 2/34) of the strains was impossible. Moreover, 20.59% (n = 7/34) were positive to the clonal groups ST117, 8.82% (n = 3/34) to ST95, and 8.82% (n = 3/34) were classified as belonging to serogroup O78 by PCR screening. Strains of APEC from O78 serogroup and ST117 are considered high-risk clones for poultry, and our data reinforced the need for surveillance of these pathogens in poultry farms and slaughterhouses.

Asunto(s)

Infecciones por Escherichia coli , Enfermedades de las Aves de Corral , Animales , Escherichia coli , Pollos , Filogenia , Brasil/epidemiología , Enfermedades de las Aves de Corral/epidemiología , Enfermedades de las Aves de Corral/microbiología , Infecciones por Escherichia coli/epidemiología , Infecciones por Escherichia coli/veterinaria , Infecciones por Escherichia coli/microbiología

RESUMEN

DiGeorge syndrome is a disorder caused by a microdeletion on the long arm of chromosome 22. Approximately 1% of patients diagnosed with DiGeorge syndrome may have an absence of a functional thymus, which characterizes the complete form of the syndrome. These patients require urgent treatment to reconstitute T cell immunity. Thymus transplantation is a promising investigational procedure for reconstitution of thymic function in infants with congenital athymia. Here, we demonstrate a possible optimization of the preparation of thymus slices for transplantation through prior depletion of thymocytes and leukocyte cell lineages followed by cryopreservation with cryoprotective media (5% dextran FP 40, 5% Me2SO, and 5% FBS) while preserving tissue architecture. Thymus fragments were stored in liquid nitrogen at -196°C for 30 days or one year. The tissue architecture of the fragments was preserved, including the distinction between medullary thymic epithelial cells (TECs), cortical TECs, and Hassall bodies. Moreover, depleted thymus fragments cryopreserved for one year were recolonized by intrathymic injections of 3×106 thymocytes per mL, demonstrating the capability of these fragments to support T cell development. Thus, this technique opens up the possibility of freezing and storing large volumes of thymus tissue for immediate transplantation into patients with DiGeorge syndrome or atypical (Omenn-like) phenotype.

RESUMEN

Introduction: Microbial systems, such as Escherichia coli, as host recombinant expression is the most versatile and the cheapest system for protein production, however, several obstacles still remain, such as recovery of soluble and functional proteins from inclusion bodies, elimination of lipopolysaccharides (LPS) contamination, incomplete synthesis, degradation by proteases, and the lack of post-translational modifications, which becomes even more complex when comes to membrane proteins, because they are difficult not only to produce but also to keep in solution in its active state. T-cell Immunoglobulin and Mucin domain 3 (TIM-3) is a type I transmembrane protein that is predominantly expressed on the surface of T lymphocytes, natural killer (NK) cells, dendritic cells, and macrophages, playing a role as a negative immune checkpoint receptor. TIM-3 comprises a single ectodomain for interaction with immune system soluble and cellular components, a transmembrane domain, and a cytoplasmic tail, responsible for the binding of signaling and scaffolding molecules. TIM-3 pathway holds potential as a therapeutic target for immunotherapy against tumors, autoimmunity, chronic virus infections, and various malignancies, however, many aspects of the biology of this receptor are still incompletely understood, especially regarding its ligands. Methods: Here we overcome, for the first time, the challenge of the production of active immune checkpoint protein recovered from bacterial cytoplasmic inclusion bodies, being able to obtain an active, and non-glycosylated TIM-3 ectodomain (TIM-3-ECD), which can be used as a tool to better understand the interactions and roles of this immune checkpoint. The TIM-3 refolding was obtained by the association of high pressure and alkaline pH. Results: The purified TIM-3-ECD showed the correct secondary structure and was recognized from anti-TIM-3 structural-dependent antibodies likewise commercial TIM-3-ECD was produced by a mammal cells system. Furthermore, immunofluorescence showed the ability of TIM-3-ECD to bind to the surface of lung cancer A549 cells and to provide an additional boost for the expression of the lymphocyte activation marker CD69 in anti-CD3/CD28 activated human PBMC. Discussion: Taken together these results validated a methodology able to obtain active checkpoint proteins from bacterial inclusion bodies, which will be helpful to further investigate the interactions of this and others not yet explored immune checkpoints.

RESUMEN

INTRODUCTION AND OBJECTIVES: Unsupervised PA interventions might have a role in the management of chronic obstructive pulmonary disease (COPD) but their effectiveness is largely unknown. Thus, we aimed to identify and synthesise data on the effects of unsupervised PA interventions in people with COPD. MATERIAL AND METHODS: Databases were systematically searched in April 2020, with weekly updates until September 2021. Randomised controlled trials and quasi-experimental studies comparing unsupervised PA with usual care, were included. Primary outcomes were dyspnoea, exercise capacity and physical activity. The effect direction plot was performed to synthesise results. Meta-analysis with forest plots were conducted for the Chronic Respiratory Disease questionnaire - dyspnoea domain (CRQ-D), 6-minute walk distance (6MWD) and incremental shuttle walk distance (ISWD). RESULTS: Eleven studies with 900 participants with COPD (68±10 years; 58.8% male, FEV1 63.7±15.8% predicted) were included. All interventions were conducted at home, most with daily sessions, for 8-12 weeks. Walking was the most common component. The effect direction plot showed that unsupervised PA interventions improved emotional function, fatigue, health-related quality of life, muscle strength and symptoms of anxiety and depression. Meta-analysis showed statistical, but not clinical, significant improvements in dyspnoea (CRQ-D, MD=0.12, 95% CI 0.09-0.15) and exercise capacity, measured with 6MWD (MD=13.70, 95% CI 3.58-23.83). Statistical and clinical significant improvements were observed in exercise capacity, measured with ISWD (MD=58.59, 95% CI 5.79-111.39). None to minor adverse events and a high adherence rate were found. CONCLUSIONS: Unsupervised PA interventions benefits dyspnoea and exercise capacity of people with COPD, are safe and present a high adherence rate. Unsupervised PA interventions should be considered for people with COPD who cannot or do not want to engage in supervised PA interventions or as a maintenance strategy of PA levels.

RESUMEN

BACKGROUND: Myelodysplastic Syndrome (MDS) with isolated deletion 5q is associated with a low risk to leukemic evolution and long overall survival (OS); it comprises 3%-4.5% of MDS cases in Latin America classified according to the World Health Organization 2008. This study aims to describe clinical, laboratory and the outcome of patients according to the newest World Health Organization 2016 proposal. METHODS: We retrospectively reviewed patients from four Brazilian (BR) and four Argentinean (AR) centers diagnosed between 1999 and 2019. RESULTS: The 58 patients (16-AR and 42-BR) presented a median age of 67 (IQR 61-75) years old, women predominance (70.7%) and transfusion dependency (62.5%) at diagnosis. Median hemoglobin level was 8.1g/dL, 27.5% and 44.4% presented thrombocytosis and neutropenia, respectively. Bone marrow (BM) was predominantly hypercellular (43.1%) with 66% showing dysplasia >1 lineage and 37.9% with >2% of blasts. Deletion 5q was mostly isolated (79.3%) and a variety of abnormalities were observed in remaining cases. Most patients were treated with erythropoietin-stimulating agents (ESA), 18 with lenalidomide and 15 with thalidomide. Median follow-up was 7.6 years, with a median OS of 3.5 years and an 8-years leukemic evolution rate of 18.4%. Multivariate analysis showed that age >75 years (HR 2.19), ECOG ≥2 (HR 5.76), BM blasts >2% (HR 2.92) and lenalidomide treatment (HR 0.25) independently influenced the OS. CONCLUSION: Older age, worse performance status and higher percentage of blasts, that can be easily assessed, were associated to a worse prognosis. Also, our results corroborate the protective influence of lenalidomide in terms of OS in this South American series.

Asunto(s)

Cromosomas Humanos Par 5/genética , Lenalidomida/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Factores de Edad , Anciano , Deleción Cromosómica , Femenino , Humanos , Lenalidomida/farmacología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento

RESUMEN

Haploidentical hematopoietic-cell transplantation using post-transplant cyclophosphamide(Haplo-PTCy) is a feasible procedure in children with haematologic malignancies. However, data of a large series of children with acute leukaemia(AL) in this setting is missing. We analysed 144 AL Haplo-PTCy paediatric recipients; median age was 10 years. Patients had acute lymphoblastic(ALL; n = 86) or myeloblastic leukaemia(AML; n = 58) and were transplanted in remission(CR1: n = 40; CR2: n = 57; CR3+: n = 27) or relapse (n = 20). Bone marrow was the graft source in 57%; donors were father (54%), mother (35%), or sibling (11%). Myeloablative conditioning was used in 87%. Median follow-up was 31 months. At day +100, cumulative incidence (CI) of neutrophil recovery and acute GVHD (II-IV) were 94% and 40%, respectively. At 2-years, CI of chronic GVHD and relapse, were 31%, 40%, and estimated 2-year overall survival (OS), leukaemia-free survival (LFS) and graft-versus-host-relapse-free survival (GRFS) were 52%, 44% and 34% respectively. For patients transplanted in remission, positive measurable residual disease (MRD) prior to transplant was associated with decreased LFS (p = 0.05) and GRFS (p = 0.003) and increased risk of relapse (p = 0.02). Mother donor was associated with increased risk of chronic GVHD (p = 0.001), decreased OS (p = 0.03) and GRFS (p = 0.004). Use of PBSC was associated with increased risk of chronic GVHD (p = 0.04). In conclusion, achieving MRD negativity pre-transplant, avoiding use of mother donors and PBSC as graft source may improve outcomes of Haplo-PTCy in children with AL.

Asunto(s)

Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Células Madre de Sangre Periférica , Niño , Ciclofosfamida/uso terapéutico , Femenino , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Leucemia Mieloide Aguda/complicaciones , Madres , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Acondicionamiento Pretrasplante/métodos , Trasplante Haploidéntico/efectos adversos

RESUMEN

BACKGROUND: Menopausal transition is a physiological process encompassing hormonal and body changes that impact women's health and life quality. This period may be characterized by the Stages of Reproductive Aging Workshop (STRAW + 10) criteria using menstrual patterns. Use of the STRAW + 10 is uncertain in HIV infection. We aimed to characterize menopausal transition in women with HIV (WWH) using the STRAW + 10 criteria, hormonal measures and menopause symptoms. METHODS: We performed a cross-sectional study, nested to the HIV-Infected Women's Cohort, in Rio de Janeiro, Brazil. Eligible women included those aged 30 years or older, without clinical or surgical menopause, hormonal contraception, replacement therapy and ovarian disorders. We conducted face-to-face interviews and collected blood samples for follicle stimulating hormone (FSH) and estradiol measures. RESULTS: We enrolled 328 WWH (28.3% of women in the cohort). The distribution of age, hormonal levels and reported symptoms per each STRAW + 10 stage was consistent with the expected distribution in the menopausal transition. Age and FSH significantly increased and estradiol decreased from stage -2 (7 + days of menstrual delay) to stage +2 (8 + years of amenorrhea). CONCLUSIONS: The present results support use of the STRAW + 10 to characterize the menopausal transition of WWH with good clinical and immunological control.

Asunto(s)

Envejecimiento/fisiología , Infecciones por VIH/fisiopatología , VIH , Menopausia/fisiología , Adulto , Brasil , Estudios de Cohortes , Estudios Transversales , Estradiol/sangre , Femenino , Hormona Folículo Estimulante/sangre , Humanos , Persona de Mediana Edad

RESUMEN

PURPOSE: It is postulated that patients with different types of pituitary neuroendocrine tumors (PitNETs) may present a higher incidence of cancer. Factors underlying individuals becoming overweight, such as insulin resistance, hyperleptinemia, and low-grade inflammation, may play a role in the risk of differentiated thyroid carcinoma (DTC) in such patients. This study aimed to investigate the frequency of and obesity-related risk factors associated with DTC in patients with PitNETs. METHODS: This cross-sectional study involved 149 patients with nonacromegalic PitNETs (AG group), 71 patients with acromegaly (ACRO group), and 156 controls (CG group). All participants underwent insulin and blood glucose measurements with the determination of the homeostatic model assessment-insulin resistance (HOMA-IR) index, leptin, and high-sensitivity C-reactive protein (hsCRP), and they also underwent thyroid ultrasound. Clinically significant nodules were biopsied for subsequent cytopathological evaluation, and participants were operated on when indicated. RESULTS: Patients in the AG group had high levels of insulin resistance and significantly higher levels of leptin and hsCRP compared with those of patients in the ACRO group. There were no cases of DTC in the AG group; two findings, one incidental, of DTC occurred in the CG group, and three cases of DTC were present in the ACRO group. Acromegaly was associated with DTC after adjusted analysis. CONCLUSIONS: Our findings in patients with nonacromegalic PitNETs do not indicate a high risk for DTC despite the presence of metabolic and inflammatory risk factors for neoplastic events. In contrast, acromegaly promotes a greater risk of DTC.

Asunto(s)

Adenocarcinoma/etiología , Factores de Riesgo Cardiometabólico , Inflamación/complicaciones , Tumores Neuroendocrinos/complicaciones , Neoplasias Hipofisarias/complicaciones , Neoplasias de la Tiroides/etiología , Acromegalia/complicaciones , Acromegalia/epidemiología , Acromegalia/metabolismo , Adenocarcinoma/epidemiología , Adenocarcinoma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Glucemia/metabolismo , Brasil/epidemiología , Estudios de Casos y Controles , Estudios Transversales , Femenino , Humanos , Incidencia , Inflamación/epidemiología , Inflamación/metabolismo , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/epidemiología , Tumores Neuroendocrinos/metabolismo , Neoplasias Hipofisarias/epidemiología , Neoplasias Hipofisarias/metabolismo , Factores de Riesgo , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/metabolismo , Adulto Joven

RESUMEN

Mucositis is an inflammation of the gastrointestinal mucosa resulting from high doses of radio/chemotherapy treatment and may lead to interruption of antineoplasic therapy. Soluble fibres, like pectin, increase SCFA production, which play a role in gut homoeostasis and inflammation suppression. Due to the properties of pectin, the aim of the present study was to evaluate the effect of a high-fibre (HF) diet on chemotherapy-induced mucositis in a murine model. C57/BL6 mice received control (AIN93M), HF, low/zero fibre (LF) diets for 10 d prior to mucositis challenging with irinotecan (75 mg/kg), or they were treated with acetate added to drinking water 5 d prior to and during the mucositis induction. Mice that received the HF diet showed decreased immune cells influx and improved histopathological parameters in the intestine, compared with mice that received the normal diet. Furthermore, the HF diet decreased intestinal permeability induced in the mucositis model when compared with the control group. This effect was not observed for acetate alone, which did not improve gut permeability. For instance, mice that received the LF diet had worsened gut permeability, compared with mice that received the normal diet and mucositis. The effects of the HF and LF diets were shown to modulate the intestinal microbiota, in which the LF diet increased the levels of Enterobacteriaceae, a group associated with gut inflammation, whereas the HF diet decreased this group and increased Lactobacillus and Bifidobacterium (SCFA producers) levels. In conclusion, the results demonstrated the importance of dietary fibre intake in the modulation of gut microbiota composition and homoeostasis maintenance during mucositis in this model.

Asunto(s)

Antineoplásicos , Fibras de la Dieta/administración & dosificación , Mucositis , Animales , Antineoplásicos/efectos adversos , Modelos Animales de Enfermedad , Inflamación , Ratones , Mucositis/inducido químicamente , Pectinas

RESUMEN

Resumen El objetivo de esta investigación es la modelación del dominio de un marco técnico de compartición e interacción de un expediente clínico electrónico (ECE) entre diversas instituciones de salud, públicas o privadas, como primer paso para lograr un marco técnico de refererencia para la interoperabilidad de sistemas de ECE en México. Se ha utilizado el proceso sistemático KMOS-RE para obterner los diversos artefactos que conforman el modelo: el léxico extendido del conocimiento del domino, los modelos conceptuales del dominio de aplicación y del dominio de la solución y los modelos de estados. Debido a que el diseño e implementación de los sistemas de ECE de cada una de las instituciones de salud se generan de manera independiente, realizar un marco técnico de referencia representa un gran desafío y una gran oportunidad, ya que ofrecerá ventajas importantes, como el hecho de contar con la información clínica de manera oportuna en cualquier institución de salud, la posibilidad de que el propio paciente acceda a su información y la facilidad de realizar investigación clínica a partir de los datos compartidos. Aún cuando la modelación de un dominio es dinámica, el contar con un modelo del dominio lo más preciso posible en este punto, facilitará los siguientes pasos para lograr el marco técnico de referencia propuesto.

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Abstract This paper presents the domain modeling of a technical framework of sharing and interaction of an electronic medical record among different healthcare institutions, both public or private, as a first step to establish a technical reference framework for the interoperability of electronic medical record systems in Mexico. The artefact that make up the domain model were carried out using the KMOS-RE systematic process. Through this process, the following components have been obtained: the knowledge domain extended lexicon, the conceptual models, one for the application domain and another for the solution domain, as well as the state models. Since the design and implementation of the electronic medical record systems of different healthcare institutions are generated independently, having a technical reference framework represents a great challenge but also a great opportunity, since it will offer important advantages, such as having the clinical information in a timely manner in any healthcare institution, the possibility of the patient accessing their own information and the ease of conducting clinical research from the shared data. Even when a domain modeling is a dynamic task, having a precise domain model at this point will facilitate the next steps to achieve the proposed technical reference framework.

RESUMEN

[This corrects the article DOI: 10.1371/journal.pone.0219857.].

RESUMEN

BACKGROUND: The risk of recurrence of solitary plasmacytoma (SP)/progression to MM is well established, but patient, imaging and treatment factors influencing risk of progression require further evaluation. METHODS: This is a retrospective analysis of 66 SP patients (23 UK, 43 Brazil) diagnosed 1989-2016. Patient baseline characteristics were recorded. The incidence of progression to MM was calculated, including biochemical and imaging findings and the treatment modality received. Survival estimates were determined by Kaplan-Meier analyses. RESULTS: With a median follow-up of 53.6 months the 5 year overall survival (OS) was 90.7% (95%CI 79-96%). The median progression free survival (PFS) from diagnosis was 61 months. Cumulative incidence of progression to MM was 49.9% at 5 years (95% CI 35.6-62.6%) and was significantly higher with bone plasmacytoma (47.2%, 95%CI 31.9-61.1%), than an extramedullary location (8.3%, 95%CI 0.4-32.3%, Gray test p = 0.0095)). The majority of patients with solitary bony plasmacytoma (SBP) received radiotherapy (RT) (51/53, 96.2%) whereas most extramedullary cases were treated with surgical resection (7/13, 53.8%). A small proportion of SBP patients received additional upfront chemotherapy, with 5/6 in remission after a median follow-up (FU) of 10 years. The diagnostic yield of surveillance functional FU imaging without other indications of relapse/progression was low. The positive predictive value of functional FU imaging was high but with a low negative predictive value, especially in cases of suspected relapse/progression. CONCLUSION: Our data suggests functional imaging should be used if clinical suspicion of relapse/progression, rather than a routine surveillance tool, and upfront adjuvant chemotherapy is worthy of prospective evaluation.

Asunto(s)

Plasmacitoma/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/normas , Adolescente , Adulto , Anciano , Quimioterapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Plasmacitoma/epidemiología , Plasmacitoma/terapia , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Valor Predictivo de las Pruebas , Radiofármacos , Radioterapia , Análisis de Supervivencia

RESUMEN

OBJECTIVES: To investigate attrition at the finally selected donor stage among British Bone Marrow Registry (BBMR) donors, all recruited from blood donors. BACKGROUND: The success of searches for unrelated stem cell donors relies on the existence of large international donor registries and the availability of registered donors when matched with a patient. Withdrawal of donors may adversely affect patient outcomes. MATERIALS/METHODS: Data on 2942 planned donations were analysed to assess donor-related deferral rates and associated factors. RESULTS: Overall, 20·2% of requests were cancelled. Transplant centres activated more than half of the cancellations (52·6%). Donor reasons accounted for 46·7% of cancellations (9·4% of requests), of which 61·7% happened for medical and 38·3% for personal reasons. Medical ineligibility of the donor was associated with increasing age (odds ratio [OR] = 1·36, P = 0·011) and peripheral blood stem cell source (OR = 2·22, P = 0·006), and there was some evidence of association with low blood donation reliability (OR = 1·52, P = 0·054). The blood donor reliability score relates to blood donation, and the score worsens if donors consistently fail to attend a donation session when invited. Withdrawal on personal grounds showed associations with donor age (OR = 1·72, P = 0·017, 30-40 years vs other ages), peripheral blood stem cell source (OR = 2·43, P = 0·010) and low blood donor reliability (OR = 1·94, P = 0·007). CONCLUSIONS: To our knowledge, this is the first report on all-cause cancellation at the finally-selected donor stage for international stem cell donor provision, showing 9·4% donor-related cancellation rate. Scores associated with blood donation reliability may be useful to predict stem cell donor withdrawal.

Asunto(s)

Selección de Donante , Células Madre de Sangre Periférica , Sistema de Registros , Donantes de Tejidos , Adulto , Factores de Edad , Médula Ósea , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reino Unido